Amino derivatives of [4,3-c]pyrazolopyridine carboxylic acids and esters

ABSTRACT

New amino derivatives of pyrazolo[4,3-c]pyridine-7-carboxylic acids and esters have the general formula ##SPC1## 
     Wherein R is hydrogen or lower alkyl; R 1  is hydrogen, lower alkyl, phenyl or phenyl--(C 1  -C 2 )-- lower alkyl; R 2  is hydrogen, lower alkyl, phenyl or phenyl--(C 1  -C 2 )-- lower alkyl; the group ##EQU1## forms one of the heterocyclic groups aziridono, pyrrolidino, piperidino, piperazino, 4-lower alkylpiperazino or 4-(hydroxy-lower alkyl)piperazino; R 5  is hydrogen, lower alkyl or phenyl; and physiologically acceptable acid addition salts thereof. 
     They are useful as ataractic, analgesic and antiinflammatory agents. In addition, the new compounds increase the intracellular concentration of adenosine-3&#39;,5&#39;-cyclic monophosphate.

This application is a division of application Ser. No. 263,566, filedJune 16, 1972, U.S. Pat. No. 3,835,144, issued Sept. 10, 1974.

SUMMARY OF THE INVENTION

This invention relates to new amino derivatives ofpyrazolo[4,3-c]pyridine-7-carboxylic acids, their esters and salts ofthese compounds as well as processes for producing them. These newcompounds have the formula ##SPC2##

The symbols have the following meanings in formula I and throughout thisspecification. R is hydrogen or alkyl up to 12 carbon atoms, R₁ ishydrogen, lower alkyl, benzoyl, substituted benzoyl (wherein the phenylring bears one or two substituents named below), phenyl or phenyl loweralkyl. R₂ is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl. Thebasic nitrogen group ##EQU2## is an acyclic amino moiety wherein R₃ andR₄ each is hydrogen, lower alkyl, phenyl, substituted phenyl (i.e., thephenyl ring contains one or two simple substituents, preferably loweralkyl, halogen, especially chlorine or trifluoromethyl), phenyl-loweralkyl, di-lower alkylamino-lower alkyl or cyclo-lower alkyl. R₅ ishydrogen, lower alkyl or phenyl.

The basic group may also form a heterocycle of 3-, 5- or 6-members inwhich an additional nitrogen is present, i.e., the aziridinyl,pyrrolidino, piperidino, pyrazolyl, pyrimidyl, pyridazinyl orpiperazinyl radicals each of which may also bear as a substituent ahydroxy-lower alkyl group or one or two lower alkyl groups.

The lower alkyl groups in any of the foregoing radicals are straight orbranched chain hydrocarbon groups of up to seven carbon atoms likemethyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. Thecyclo-lower alkyl groups are the three to six carbon alicyclics,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially the lasttwo.

Especially preferred compounds of formula I are those wherein R ishydrogen or lower alkyl, especially ethyl, R₁ is hydrogen or ethyl, R₂is methyl, R₃ is ethyl, propyl or butyl, R₄ is hydrogen and R₅ ishydrogen, methyl or ethyl. The examples illustrate other preferredembodiments.

DETAILED DESCRIPTION

The new compounds of formula I may be produced by the following method.

A 5-aminoisoxazole of the formula ##SPC3##

[produced by reacting 3-iminobutyronitrile with hydroxylamine by theprocedure described in Ann. Chem. 624, 22 (1959)] is made to react withan alkoxymethylene malonic acid ester of the formula ##EQU3## by heatingat a temperature of about 120° C.

The resulting compound of the formula ##SPC4##

is cyclized in an inert organic solvent, while distilling off thealcohol formed producing a compound of the formula ##SPC5##

This is then alkylated by treatment with an alkyl halide in an inertorganic solvent like dimethylformamide in the presence of an alkalimetal carbonate to obtain a compound of the formula ##SPC6##

The compound of formula V instead of being alkylated may be refluxed forseveral hours with a phosphorus halide like phosphorus oxychloride toobtain the intermediate of the formula ##SPC7##

Alternatively, instead of cyclizing the malonic acid ethyl estercompound of formula IV in an inert organic solvent at about 230° to 260°C, this product also undergoes cyclization by means of phosphorusoxychloride producing directly the intermediate of formula VII.

The intermediate of formula VI or of formula VII is then made to reactwith an amine ##EQU4## wherein R₆ and R₇ each is hydrogen, or analiphatic group like methyl, ethyl and the like. This reaction yields acompound of the formula ##SPC8##

The compound of formula VIII is then hydrogenated with a catalyst likePd on charcoal in an organic solvent like acetic acid to form a compoundof the formula ##SPC9##

Treatment of the compound of formula IX with hydrazine yields a compoundof the formula ##SPC10##

which may be alkylated with an alkyl halide in an inert organic solventin the presence of an alkali metal carbonate producing a compound of theformula ##SPC11##

Instead of alkylating, the compound of formula X may be refluxed with aninorganic metal halide, like phosphorus oxychloride, to obtain acompound of the formula ##SPC12##

Compounds of formula I are now produced by reacting either compounds offormula XI or XII with an appropriate amine of the formula ##EQU5## atelevated temperatures.

Products of formula I with R₁ other than hydrogen are produced fromcompounds of formula I with R₁ = H, as described above, by alkylatingwith a compound of the formula R₁ -hal, wherein R₁ has one of the abovedefined meanings other than hydrogen, in the presence of a strong baselike sodium hydride. Compounds of formula I wherein R is hydrogen areformed from the alkyl esters by conventional hydrolysis, e.g., bytreatment with a base such as sodium hydroxide.

The compounds of formula I form salts which are also part of thisinvention. The salts include acid-addition salts, particularly thenon-toxic, physiologically acceptable members. The bases of formula Iform salts by reaction with a variety of inorganic or organic acidsproviding acid addition salts including, for example, hydrohalides(especially hydrochloride and hydrobromide), sulfate, nitrate, borate,phosphate, oxalate, tartrate, maleate, citrate, acetate, ascorbate,succinate, benzenesulfonate, methanesulfonate, cyclohexanesulfamate andtoluenesulfonate. The acid addition salts frequently provide aconvenient means for isolating the product, e.g., by forming andprecipitating the salt in an appropriate menstruum in which the salt isinsoluble, then after separation of the salt, neutralizing with a basesuch as barium hydroxide or sodium hydroxide, to obtain the free base offormula I. Other salts may then be formed from the free base by reactionwith an equivalent of acid.

The new compounds of this invention are central nervous systemdepressants and may be used as tranquilizers or ataractic agents for therelief of anxiety and tension states, for example, in mice, cats, rats,dogs, and other mammalian species, in the same manner aschlordiazepoxide. For this purpose a compound or mixture of compounds offormula I, or non-toxic, physiologically acceptable acid addition saltthereof, may be administered orally or parenterally in a conventionaldosage form such as tablet, capsule, injectable or the like. A singledose, or preferably 2 to 4 divided daily doses, provided on a basis ofabout 3 to 40 mg. per kilogram per day, preferably about 3 to 15 mg. perkilogram per day, is appropriate. These may be conventionally formulatedin an oral or parenteral dosage form by compounding about 10 to 250 mg.per unit of dosage with conventional vehicle, excipient binder,preservative, stabilizer, flavor or the like as called for by acceptedpharmaceutical practice.

The new compounds also increase the intracellular concentration ofadenosine-3',5'-cyclic monophosphate, and thus by the administration ofabout 5 to 100 mg/kg/day, preferably about 10 to 50 mg/kg, in single ortwo to four divided doses in conventional oral or parenteral dosageforms such as those described above may be used to alleviate thesymptoms of asthma.

The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale.

EXAMPLE 1 4-Butylamino-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylicacid ethyl ester

a. [[(3-Methyl-5-isoxazolyl)amino]methylene]malonic acid diethyl ester

112.5 g. of 3-Methyl-5-aminoisoxazole (1.14 mol.) and 248 g. ofethoxymethylenemalonic acid diethyl ester (1.14 mol.) are heated withstirring for 45 minutes at 130°. After this period, ethanol is removedunder reduced pressure. The residue solidifies on cooling and isrecrystallized from ethanol, m.p. 134°-136°, yield 245 g. (80%).

b. 4-Hydroxy-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethylester

50 g. of [[(3-methyl-5-isoxazolyl)amino]methylene]-malonic acid diethylester (0.19 mol.) are quickly added to 250 ml. of vigorously refluxingdiphenyl ether. After 7 minutes, the reaction mixture is cooled rapidly.The solvent is distilled off in vacuo and the oily residue crystallizesafter adding 100 ml. of methanol. Recrystallization from methanol yields20 g. (48%) of 4-hydroxy-3-methylisoxazolo[5,4-b]pyridine-5-carboxylicacid ethyl ester, m.p. 150°-152°.

c. 4-Ethoxy-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethylester

2.22 g. of 4-Hydroxy-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acidethyl ester (0.1 mol.) are dissolved in 150 ml. of ethanol and 28 g. ofpotassium carbonate (0.2 mol.). 31 g. of ethyl iodide (0.2 mol.) areadded. The mixture is heated with stirring for 6 hours. The hot solutionis filtered and the solvent evaporated. The oily residue yields oncrystallization with methanol 18.2 g. of4-ethoxy-3-methylisoxazolo-[3,4-b]pyridine-5-carboxylic acid ethyl ester(73%), m.p. 62°.

d. 4-Butylamino-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethylester

25 g. of 4-ethoxy-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acidethyl ester (0.113 mol.) are dissolved in 100 ml. of benzene and afteradding 8 g. of butylamine (0.23 mol.), the solution is refluxed for 12hours. The solvent is distilled off and the residual4-butylamino-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethylester is recrystallized from ligroin, m.p. 60°, yield 23.5 g. (85%).

e. 3-Acetyl-4-butylamino-2-hydroxypyridine-5-carboxylic acid ethyl ester

300 g. of 4-butylamino-3-methylisoxazolo[5,4-b]pyridine-5-carboxylicacid ethyl ester (1.08 mol.) are dissolved in 0.5 liter of acetic acid.1 g. of palladium on charcoal is added and the mixture is hydrogenated.After absorption of 24 liters of hydrogen, the reaction is stopped, thecatalyst is filtered off and the solvent removed in vacuo. The remainingresidue is treated for 7 hours at 100° with 0.5 liter of water whilestirring. The reaction mixture is cooled and extracted three times with200 ml. portions of chloroform. The organic layers are collected, driedover sodium sulfate and evaporated to dryness. Recrystallization of theoily residue yields 216 g. of3-acetyl-4-butylamino-2-hydroxypyridine-5-carboxylic acid ethyl ester(72%), m.p. 134°-136°.

f. 4-Hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethylester

8.4 g. of 3-acetyl-4-butylamino-2-hydroxypyridine-5-carboxylic acidethyl ester (0.03 mol.) are dissolved in 20 ml. of acetic acid, 3 ml. ofhydrazine-hydrate are added and the mixture is refluxed for 5 hours.After this time, the solvent is removed in vacuo and the crystallineprecipitate of4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethylester is recrystallized from acetic acid, yield 5.1 g. (77%), m.p. 310°.

g. 4-Ethoxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethylester

2.2g. of 4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acidethyl ester (0.01 mol.), 2.8 g. of potassium carbonate (0.02 mol.), and1.6 g. of ethyl iodide (0.01 mol.) are suspended in 50 ml. ofdimethylformamide and heated for 10 hours at 70°. After this time, themixture is acidified with acetic acid and 30 ml. of water are added.4-Ethoxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethylester precipitates, is filtered and recrystallized from methanol, yield1.9 g. (79%), m.p. 200°.

h. 4-Butylamino-3-methyl-1H-pyrazolo[4,3-c]-pyridine-7-carboxylic acidethyl ester

2.5 g. of 4-ethoxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acidethyl ester (0.01 g.) are refluxed with 10 ml. of butylamine for 12hours. After this time, the excess butylamine is distilled off and theresidue recrystallized from pettroleum ether, yield 1.9 g. (68%), m.p.99°-100°. The hydrochloride is formed by adding to the product in ethersolution an alcoholic solution of hydrogen chloride.

EXAMPLE 24-Diethylamino-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acidethyl ester

a. 4-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethylester

22.1 g. of 4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylicacid ethyl ester (0.1 mol.) and 100 ml. of phosphorus oxychloride arerefluxed for 10 hours. After this time, the excess phosphorusoxychloride is removed by distillation. The oily residue is poured into50 ml. of ice water. On neutralization with aqueous ammonia,4-chloro-3-methyl-1H-pyrazolo[4,3-c]-pyridine-7-carboxylic acid ethylester crystallizes and is filtered. Recrystallization yields 12 g.(50%), m.p. 180°.

b. 4-Diethylamino-3-methyl-1H-pyrazolo[4,3-c]-pyridine-7-carboxylic acidethyl ester

2.4 g. of 4-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acidethyl ester is refluxed with 20 ml. of diethylamine for 24 hours. Theexcess diethylamine is removed by distillation and the residue treatedwith 20 ml. of water.4-Diethylamino-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acidethyl ester precipitates and is recrystallized from ethyl acetate. Yield2.1 g. (76%), m.p. 85°-88°. Hydrolysis of this product with aqueoussodium hydroxide yields4-diethylamino-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid.

The following additional compounds are produced by the procedure ofExample 1: ##SPC13##

    Example                                                                            R.sub.1        R.sub.2                                                                            R.sub.3       R.sub.4  R.sub.5                                                                            R                        __________________________________________________________________________    3    CH.sub.3 --CH.sub.2                                                                          CH.sub.3                                                                           CH.sub.3 --CH.sub.2                                                                         CH.sub.3 --CH.sub.2                                                                    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5          4    CH.sub.3 --CH.sub.2                                                                          H    --CH.sub.2 --CH.sub.2 --N--CH.sub.2 --CH.sub.2                                --                     H    C.sub.2 H.sub.5                                   |                                                                    CH.sub.3                                             5    CH.sub.3 --CH.sub.2                                                                          H    --(CH.sub.2).sub.3 N(C.sub.2 H.sub.5).sub.2                                                 H        H    C.sub.2 H.sub.5          6    CH.sub.3 --CH.sub.2                                                                          H    --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2                                   --CH.sub.2 --          H    C.sub.2 H.sub.5          7    CH.sub.3 --CH.sub.2                                                                          H    CH.sub.3 --CH.sub.2                                                                         CH.sub.3 --CH.sub.2                                                                    H    C.sub.2 H.sub.5          8    CH.sub.3 --CH.sub.2                                                                          H    --(CH.sub.2).sub.2 N(C.sub.2 H.sub.5).sub.2                                                 H        H    C.sub.2 H.sub.5          9    CH.sub.3 --CH.sub.2                                                                          CH.sub.3                                                                           H             H             C.sub.2 H.sub.5          10   CH.sub.3 --CH.sub.2                                                                          H    CH.sub.3 CH.sub.3      H    C.sub.2 H.sub.5                                   ||                                                          --CH.sub.2 --C=CH--C=N--                             11   CH.sub.3 --CH.sub.2                                                                          CH.sub.3                                                                           --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2                                   --CH.sub.2 --          C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5          12   CH.sub.3 --CH.sub.2                                                                          CH.sub.3                                                                           --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2                                                          H-   C.sub.2 H.sub.5          13   CH.sub.3 --CH.sub.2                                                                          H    --CH.sub.2 --CH.sub.2 --N--CH.sub.2 --CH.sub.2                                --                     H    C.sub.2 H.sub.5                                   |                                                                    CH.sub.2 --CH.sub.2 --OH                             14   CH.sub.3 --CH.sub.2                                                                          H    H             H        H    H                        15   CH.sub.3       H    -- (CH.sub.2).sub.3 CH.sub.3                                                                H        H    H                        16   CH.sub.3       H    --(CH.sub.2).sub.3 CH.sub.3                                                                 H        H    H                        17   CH.sub.3 --CH.sub.2                                                                          H    --(CH.sub.2).sub.3 CH.sub.3                                                                 H        H    H                        18   CH.sub.3 --CH.sub.2                                                                          CH.sub.3                                                                           H                      H    C.sub.2 H.sub.5                                   --CH=C--C=C--NH--                                                             ||                                                          CH.sub.3 CH.sub.3                                    19                  CH.sub.3                                                                           --(CH.sub.2).sub.3 CH.sub.3                                                                 H        H    C.sub.2 H.sub.5          20   H              CH.sub.3           H        H    C.sub.2 H.sub.5          21   H              H                  H        H    H                        22   H              CH.sub.3                                                                           --CH.sub.2 --CH(CH.sub.3).sub.2                                                             H        H    C.sub.2 H.sub.5                                   CH.sub.3                                             23   H              CH.sub.3                                                                           --CH∠   H        H    C.sub.2 H.sub.5                                   CH.sub.2 --CH.sub.3                                  24   H              CH.sub.3           H        H    C.sub.2 H.sub. 5         25   CH.sub.3 --CH.sub.2                                                                          CH.sub.3           H        H    C.sub.2 H.sub.5          26   H              CH.sub.3                                                                           --(CH.sub.2).sub.3 CH.sub.3                                                                 H        H    C.sub.2 H.sub.5          27   CH.sub.3 --CH.sub.2                                                                          H    --(CH.sub.2).sub.2 CH.sub.3                                                                 H        H    C.sub.2 H.sub.5          28   CH.sub.3 --CH.sub.2                                                                          H    --CH(CH.sub.3).sub.2                                                                        H        CH.sub.3                                                                           C.sub.2 H.sub.5          29   CH.sub.3 --CH.sub.2                                                                          H    --(CH.sub.2).sub.5 CH.sub.3                                                                 H        CH.sub.3                                                                           C.sub.2 H.sub.5          30   CH.sub.3 --CH.sub.2                                                                          CH.sub.3                                                                           --(CH.sub.2).sub.3 CH.sub.3                                                                 H        CH.sub.3                                                                           H                        31   CH.sub.3 --CH.sub.2                                                                          H    --C(CH.sub.3).sub.3                                                                         H             C.sub.2 H.sub.5          32   CH.sub.3 --(CH.sub.2).sub.3                                                                  H    --(CH.sub.2).sub.3 CH.sub.3                                                                 H        H    C.sub.2 H.sub.5          33   CH.sub.3 --CH.sub.2                                                                          H                  H        CH.sub.3                                                                           C.sub.2 H.sub.5          34   H              H                  H        H    H                        35   CH.sub.3 --CH.sub.2                                                                          H                  H        H    C.sub.2 H.sub.5          36   CH.sub.3 (CH.sub.2).sub.3                                                                    CH.sub.3                                                                           --(CH.sub.2).sub.3 CH.sub.3                                                                 H        H    C.sub.2 H.sub.5          37                  H    --(CH.sub.2).sub.3 CH.sub.3                                                                 H        H    C.sub.2 H.sub.5          38   H              CH.sub.3                                                                           --CH.sub.2 --CH.sub.2 --                                                                             H    C.sub.2 H.sub.5          39                  H    CH.sub.3 --(CH.sub.2).sub.3 --                                                              CH.sub.3 --                                                                            H    CH.sub.3 --CH.sub.2                                                           --                       40                  H    CH.sub.3 --CH.sub.2 --                                                                      H        H    CH.sub.3 --CH.sub.2                                                           --                       41                  CH.sub.3                                                                           CH.sub.3      CH.sub.3 --(CH.sub.2).sub.3                                                            H-   CH.sub.3 --CH.sub.2                                                           --                       42                  H    CH.sub.3 --(CH.sub.2).sub.3 --                                                              H        H    CH.sub.3 --(CH.sub.2)                                                         .sub.6 --                43   CH.sub.3 --CH.sub.2 --CH.sub.2 --                                                                 CH.sub.3 --(CH.sub.2).sub.3 --                                                              H        CH.sub.3                                                                           CH.sub.3 --CH.sub.2                               CH.sub.3                                                                      |                                           44   CH.sub.3 --CH.sub.2 --                                                                       CH.sub.3                                                                           --CH.sub.2 --CH.sub.2 --N--CH.sub.2 --CH.sub.2                                --                     H    CH.sub.3 --CH.sub.2      45   H              CH.sub.3                                                                           CH.sub.3 --(CH.sub.2).sub.3 --                                                              H             CH.sub.3 --CH.sub.2                                                           --                       46                  CH.sub.3                                                                           CH.sub.3 --(CH.sub.2).sub.3 --                                                              H        H    CH.sub.3 --CH.sub.2      47   H              CH.sub.3                                                                           CH.sub.3 --(CH.sub.2).sub.3 --                                                              H        H    H                        48   H              H    CH.sub.3 --(CH.sub.2).sub.3 --                                                              H        C.sub.2 H.sub.5                                                                    CH.sub.3 --CH.sub.2                                                           --                       49   H              H                  H        H    CH.sub.3 --CH.sub.2                                                           --                       50   H              H                  H        H    H                        __________________________________________________________________________

Other members of the class may similarly be produced by the procedure ofExample 1 by suitable substitution of the variables in the startingmaterials.

What is claimed is:
 1. A compound of the formula ##SPC14##wherein R ishydrogen or lower alkyl; R₁ is hydrogen, lower alkyl, phenyl orphenyl--(C₁ -C₂)lower alkyl; R₂ is hydrogen, lower alkyl, phenyl orphenyl--(C₁ -C₂)lower alkyl; the group ##EQU6## forms one of theheterocyclic groups aziridino, pyrrolidino, piperidino, piperazino,4-lower alkylpiperazino or 4-(hydroxy-lower alkyl)piperazino; R₅ ishydrogen, lower alkyl or phenyl; and physiologically acceptable acidaddition salts thereof.
 2. A compound as in claim 1 wherein the group##EQU7## is pyrrolidino.
 3. A compound as in claim 1 wherein the group##EQU8## is aziridino.
 4. A compound as in claim 2 wherein R, R₁ and R₂each is lower alkyl and R₅ is hydrogen.
 5. A compound as in claim 2wherein R and R₁ each is ethyl, R₂ is methyl and R₅ is hydrogen.
 6. Acompound as in claim 3 wherein R and R₂ each is lower alkyl and R and R₅each is hydrogen.
 7. A compound as in claim 3 wherein R is ethyl, R₁ andR₅ each is hydrogen and R₂ is methyl.